Chronic lymphocytic leukaemia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

CLL and small lymphocytic lymphoma are one biological disease classified by distribution. A persistent blood clonal B-cell count of at least 5 × 10⁹/L establishes CLL; tissue-predominant disease below this threshold is SLL. A smaller asymptomatic blood clone without nodes, organ enlargement or cytopenia is monoclonal B-cell lymphocytosis. Smudge cells are common but non-specific, and marrow biopsy is not routinely required to diagnose an otherwise typical blood presentation.

Rai or Binet stage describes clinical burden but does not automatically trigger treatment. Indications include worsening marrow-failure anaemia or thrombocytopenia, massive or progressive spleen or nodes, rapid progressive lymphocytosis after excluding infection and steroid effect, symptomatic extranodal disease, autoimmune cytopenia poorly responsive to standard therapy and constitutional symptoms attributable to CLL. Fatigue must be substantial and other causes excluded. Active monitoring includes education and timely review rather than pre-emptive chemotherapy.

Treatment choice is biology and comorbidity led. TP53 mutation or del(17p) predicts poor response durability from chemotherapy and favours targeted therapy. Covalent BTK inhibitors provide continuous control but require review of atrial fibrillation, bleeding, hypertension and CYP3A interactions. Venetoclax combinations offer fixed duration but demand formal tumour-lysis risk classification, hydration, urate lowering and laboratory monitoring. Anti-CD20 antibodies require hepatitis B screening and prophylaxis when indicated. Current BSH guidance and NHS commissioning determine exact first-line and relapse sequence.

Supportive care affects survival. Give influenza, COVID-19, pneumococcal and shingles vaccines according to UK guidance before profound B-cell depletion when possible; avoid live vaccines during significant immunosuppression. Do not use immunoglobulin solely for a low IgG value: recurrent serious bacterial infection despite appropriate vaccination and antibiotics plus impaired antibody levels creates the indication. New cytopenia requires haemolysis, nutritional, infection, medicine and marrow assessment before being labelled progression.

Key points

CLL requires at least 5 × 10⁹/L clonal B lymphocytes in peripheral blood persisting for at least 3 months with a characteristic flow phenotype.
First-line confirmation is blood film and flow cytometry showing a light-chain-restricted CD19-positive, CD5-positive, CD23-positive B-cell population with weak CD20 and surface immunoglobulin.
Do not treat an asymptomatic lymphocyte count: active monitoring is first-line until marrow failure, symptomatic or progressive tissue disease, refractory autoimmune cytopenia or defined B symptoms develop.
Before each treatment line, test TP53 mutation and del(17p); assess IGHV status before first treatment because these results change selection and should not be inferred from age or stage.
Targeted therapy has replaced routine chemoimmunotherapy for most adults; choose continuous BTK inhibition or fixed-duration venetoclax-based treatment from genetics, cardiac, bleeding, renal and interaction risk.
Venetoclax begins with a five-week 20, 50, 100, 200 and 400 mg daily ramp because rapid BCL2 inhibition can cause fatal tumour lysis.
Vaccinate early with non-live vaccines, screen hepatitis B before anti-CD20 therapy and assess recurrent serious infection with hypogammaglobulinaemia for prophylaxis or immunoglobulin replacement.
Rapid discordant node growth or high LDH is not routine CLL progression: use PET-CT to choose an adequate biopsy site for suspected Richter transformation.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Clonal mature B cells

CLL arises from a mature CD5-positive B-cell clone with acquired genomic and epigenetic lesions that prolong survival rather than simply accelerating proliferation.

Precursor monoclonal B lymphocytosis

Most cases are preceded by a small circulating CLL-phenotype clone; only a minority of high-count monoclonal B-cell lymphocytosis progresses each year.

Inherited susceptibility

Risk is higher in first-degree relatives and varies by ancestry, but routine germline testing and population screening are not indicated for most families.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Blood and tissue accumulation
Long-lived clonal cells accumulate in blood, marrow, nodes and spleen, producing lymphocytosis, cytopenia, organ enlargement and constitutional symptoms.
2
Microenvironmental signalling
B-cell receptor and BTK-dependent signals from lymphoid niches sustain the clone, explaining the efficacy and redistribution lymphocytosis of BTK inhibitors.
3
Immune dysregulation
Hypogammaglobulinaemia, impaired T-cell function and autoimmune targeting of blood cells cause infection, autoimmune haemolysis and immune thrombocytopenia.
4
Clonal evolution
TP53 disruption, complex genetics and acquired resistance drive refractory disease, while additional lesions can produce aggressive diffuse large B-cell transformation.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Incidental lymphocytosis

Many adults are asymptomatic and diagnosed after persistent absolute lymphocytosis on a routine FBC and characteristic flow cytometry.

Tissue burden

Painless nodes, splenic fullness, early satiety and abdominal discomfort reflect lymphoid accumulation rather than an isolated blood disorder.

Marrow and immune effects

Fatigue, infection, bruising, bleeding or jaundice may arise from infiltration, hypogammaglobulinaemia or autoimmune destruction.

Treatment-indicating symptoms

Drenching sweats, measured fever, substantial weight loss, disabling fatigue or progressive bulky disease requires attribution and specialist review.

Richter patternRed flag

A rapidly enlarging focal node, severe B symptoms or sharp LDH increase should trigger urgent transformation assessment.

Red flags requiring action

Fever, rigors, hypotension, confusion or hypoxia is sepsis until assessed; CLL causes functional antibody failure even before treatment and fever may be muted.
Rapid node growth, new severe B symptoms, extranodal mass or disproportionate LDH rise suggests Richter transformation and requires urgent PET-directed biopsy.
Jaundice, dark urine, falling haemoglobin, reticulocytosis or major thrombocytopenic bleeding suggests autoimmune cytopenia and needs same-day haematology assessment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line: FBC, film and flow cytometryFirst stepFirst line
Why
Confirm persistent clonal B lymphocytosis and characteristic phenotype.
Interpretation and limitations
Count clonal B cells rather than total lymphocytes. Typical coexpression is CD5 and CD23 with weak CD20, immunoglobulin and light-chain restriction; atypical findings require broader lymphoma testing.
02
Pretreatment TP53 and IGHV assessment
Why
Select treatment with the strongest expected durability and avoid ineffective chemotherapy.
Interpretation and limitations
Use FISH for del(17p) and sequencing for TP53 mutation before every line because clones evolve; IGHV mutation status is stable and usually tested before first therapy.
03
Cause-specific cytopenia work-up
Why
Separate marrow failure, autoimmune destruction, bleeding, deficiency, infection and medicine toxicity.
Interpretation and limitations
Use film, reticulocytes, bilirubin, LDH, haptoglobin, direct antiglobulin test and nutritional tests; marrow biopsy is appropriate when the mechanism remains unclear.
04
Selective CT or PET-directed biopsy
Why
Stage symptomatic tissue when it changes therapy and confirm suspected Richter transformation.
Interpretation and limitations
Routine serial imaging is unnecessary in stable blood-predominant disease. PET identifies a high-uptake site but histology, not uptake alone, diagnoses transformation.
05
Treatment safety baseline
Why
Prevent lysis, viral reactivation, bleeding, arrhythmia and reproductive harm.
Interpretation and limitations
Check renal, liver, calcium, phosphate, urate, LDH, immunoglobulins, hepatitis B, C and HIV, ECG and medicines; assess pregnancy, fertility and tumour burden.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Reactive lymphocytosis

Viral infection, smoking and physiological stress cause polyclonal or morphologically reactive lymphocytes; repeat counts and flow cytometry distinguish persistence and clonality.

Monoclonal B-cell lymphocytosis

A CLL-phenotype blood clone below 5 × 10⁹/L without nodes, spleen, cytopenia or symptoms is monitored as a precursor, not labelled CLL.

Small lymphocytic lymphoma

The same biological clone with tissue disease but fewer than 5 × 10⁹/L circulating clonal B cells is classified as small lymphocytic lymphoma.

Mantle-cell and other lymphoma

Mantle-cell lymphoma can be CD5 positive but cyclin D1 or SOX11 and t(11;14) testing separate a disease with different treatment.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01New persistent lymphocytosisConfirm clone and classificationFirst stepAbsolute lymphocytosis persists without a clear transient cause.

1Repeat FBC and examine the film, assess nodes, spleen, infection, cytopenia and symptoms.
2Perform flow cytometry and calculate the clonal B-cell count, expanding testing if phenotype is atypical.
3Classify CLL, SLL or monoclonal B-cell lymphocytosis and set active monitoring or a treatment-indication assessment.

02Asymptomatic CLLMonitor without treating countsConfirmed disease lacks an iwCLL treatment indication.

1Document nodal and splenic findings, FBC, infections, autoimmune history and symptom baseline.
2Use interval clinical review and FBC, with vaccination and rapid-access education rather than routine serial scans.
3Reassess early for progressive cytopenia, bulky tissue, B symptoms, autoimmune disease or a transformation pattern.

03Treatment-requiring CLLTest biology before selecting therapyMarrow failure, symptomatic progressive tissue, refractory autoimmune cytopenia or attributable B symptoms emerge.

1Confirm the indication and obtain del(17p), TP53 mutation, IGHV if not known and infection and organ baseline.
2Choose a current commissioned targeted regimen through the CLL MDT using bleeding, cardiac, renal, interaction and lysis risk.
3Apply drug-specific prophylaxis and monitoring and reassess response, minimal residual disease only where protocol relevant and treatment-emergent toxicity.

04Possible Richter transformationBiopsy the discordant lesionOne site grows rapidly with high LDH, new organ disease or severe B symptoms.

1Stabilise infection, lysis or organ compromise and arrange urgent PET-CT.
2Obtain generous core or excision tissue from the most avid safely accessible lesion before prolonged steroid when possible.
3EscalationIf aggressive lymphoma is confirmed, stage and treat through the Richter or large-cell pathway rather than escalating CLL treatment empirically.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Covalent BTK inhibition is a first-line or relapse option in defined CLL settings, including biologically high-risk disease.

Zanubrutinib

Give 320 mg orally once daily or 160 mg orally twice daily continuously until progression or unacceptable toxicity; use 80 mg twice daily in severe Child-Pugh C hepatic impairment.

Reduce to 80 mg once daily with a strong CYP3A inhibitor or 80 mg twice daily with a moderate inhibitor and avoid strong inducers. Monitor bleeding, rhythm, blood pressure, infection, monthly FBC and skin; withhold 3 to 7 days around surgery and monitor closely when CrCl is below 30 mL/min or during dialysis. Avoid pregnancy, add barrier contraception to hormonal methods and continue effective contraception for 1 month after treatment; stop breastfeeding.

BCL2 inhibition provides deep responses in fixed-duration anti-CD20 combinations and selected relapse regimens.

Venetoclax

Ramp orally once daily over 5 weeks: 20 mg in week 1, 50 mg week 2, 100 mg week 3, 200 mg week 4 and 400 mg from week 5; then use 400 mg daily for the selected 12-cycle obinutuzumab regimen, 24-month rituximab regimen or until progression or intolerance for monotherapy.

Classify tumour-lysis risk from nodes, lymphocyte count and renal function and use timed hydration, urate lowering and chemistry. Strong CYP3A inhibitors are contraindicated during ramp-up; review CYP3A and P-gp dose changes throughout and interrupt rather than guessing after a prolonged missed course. Avoid pregnancy, use effective contraception during and for 30 days after treatment, stop breastfeeding and discuss possible male fertility impairment.

A fixed-duration first-line regimen for eligible adults under current commissioning.

Obinutuzumab with venetoclax

Give obinutuzumab 100 mg intravenously day 1 and 900 mg day 2, then 1,000 mg on days 8 and 15 of cycle 1 and day 1 of cycles 2 to 6; start the venetoclax ramp on day 22 of cycle 1, then give venetoclax 400 mg daily through the last day of cycle 12.

Use exact infusion premedication and lysis debulking plan. Screen hepatitis B and provide antiviral prophylaxis when indicated; monitor infusion reaction, neutropenia, infection and venetoclax interactions.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Infection

Encapsulated bacterial infection, shingles and opportunistic pathogens reflect disease, steroids, anti-CD20 therapy, BTK inhibition and later cellular or antibody treatments.

Autoimmune cytopenia

Warm autoimmune haemolysis, immune thrombocytopenia, pure red-cell aplasia and neutropenia may occur independently of marrow infiltration and require mechanism-specific care.

Richter transformation

Transformation to aggressive lymphoma causes rapid focal growth and systemic illness; tissue confirmation is essential because treatment differs from progressive CLL.

Therapy-related harm

Tumour lysis, bleeding, atrial arrhythmia, hypertension, infection, neutropenia and second skin cancer depend on regimen and cumulative immune suppression.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During active monitoring, assess B symptoms, fatigue, infections, nodes and spleen with FBC at a tempo-based interval; do not scan routinely without a clinical question.
Before and during treatment, track FBC, renal and liver function, lysis markers, infection and regimen-specific bleeding, blood pressure, rhythm or neutropenia.
With venetoclax ramp-up, perform protocol-timed potassium, phosphate, calcium, urate and creatinine checks and escalate to inpatient monitoring for high tumour-lysis risk.
After anti-CD20 treatment, maintain hepatitis B prophylaxis and monitoring for the specialist-defined period and assess delayed neutropenia and vaccine response.
At relapse, repeat TP53 testing and confirm transformation when tempo is discordant before choosing the next commissioned class.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Count the clone

The diagnostic threshold refers to clonal B cells, not total lymphocytes, and must be interpreted with tissue disease.

Treat indications, not stage alone

A high lymphocyte count can be safely observed when stable and asymptomatic, while autoimmune or organ complications may require action at a lower count.

TP53 testing expires

Del(17p) and TP53-mutant subclones can emerge under treatment, so testing is repeated before each new line.

BTK redistribution is expected

An early blood lymphocyte rise with shrinking nodes on BTK inhibition can reflect mobilisation rather than progression.

PET selects tissue

High uptake raises suspicion for Richter transformation but only adequate biopsy establishes the diagnosis.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing CLL from smudge cells without flow cytometry.
02
Treating an asymptomatic lymphocyte count in isolation.
03
Starting therapy without current TP53 and del(17p) assessment.
04
Beginning venetoclax without formal lysis stratification and timed blood tests.
05
Calling rapid focal growth ordinary CLL progression without biopsy.
06
Giving live vaccines during substantial immune suppression.